Influenza virus is a member of the Orthomyxoviridae family. There are three types of influenza viruses, designated influenza A, influenza B, and influenza C. Influenza A viruses infect not only humans but also many species of birds and mammals and are classified by subtype of their surface proteins, hemagglutinin (HA) and neuraminidase (NA). The influenza A virion contains a segmented negative-sense RNA genome, which encodes the following proteins: hemagglutinin (HA), neuraminidase (NA), matrix (M1), proton ion-channel protein (M2), nucleoprotein (NP), polymerase basic protein 1 (PB1), PB1-F2, polymerase basic protein 2 (PB2), polymerase acidic protein (PA), PA-X, nonstructural protein 1 (NS1), and nonstructural protein 2 (NS2). The HA, NA, M1, and M2 are membrane associated, whereas NP, PB1, PB2, PA, are nucleocapsid associated proteins, and the PB1-F2, NS2, and PA-X proteins are nonstructural proteins. The HA and NA proteins are envelope glycoproteins, with HA responsible for virus attachment and penetration of the viral particles into the cell and NA responsible for viral release, and are the sources of the major immunodominant epitopes for virus neutralization and protective immunity.
The public health burden of influenza is great, with an average of >200,000 hospitalizations per year in the U.S., and resulting mortality of seasonal influenza ranging from 3,000 to 49,000 per year in the U.S. In pandemic years these totals can increase dramatically. In 1918, the worst influenza pandemic on record, 675,000 people died in the U.S. and up to 50 million people globally. Additionally, novel strains of influenza with HA and NA subtypes for which most people do not have any immunity can emerge in animals (e.g., birds and swine) and be transmitted to people. Zoonotically derived outbreaks can ensue which might lead to a pandemic. In the last few years, a swine H1N1 virus adapted to people to cause a pandemic in 2009. Bird-adapted strains of H5N1, H9N2, H7N9, H10N8, and H6N1 have all caused human infections, often with significant mortality.
Since the 2009 pandemic, zoonotic infections with H5N1, H7N9, H3N2v, and recently H6N1 and H10N8 have been observed, stressing the need for a broadly reactive or universal vaccine approach that extends beyond protection against defined circulating seasonal variants, which could help prevent or mitigate a future pandemic by serving as a pre-pandemic vaccine. Inactivated vaccines delivered intramuscularly do not generate a robust mucosal immune response, and live attenuated influenza vaccines are problematic because they are over-attenuated, have restricted usage guidelines, and also because live viruses expressing hemagglutinin (HA) and/or neuraminidase (NA) subtypes not present in seasonal strains cannot be used because of the risk of reassortment with wild type viruses. Thus there is a need for a broadly reactive vaccine that can generate a protective immune response without the requirement of employing a live attenuated virus. The major difficulty faced by universal influenza vaccine approaches is the antigenic variability of different HA and NA subtypes. A universal vaccine could serve as a pre-pandemic vaccine, providing protection against zoonotic influenza infections as well as providing protection against seasonal influenza virus strains, or both.